Tumour necrosis factor alpha as a therapeutic target for immune-mediated inflammatory diseases

Preclinical studies have identified and validated tumour necrosis factor alpha (TNFalpha) as a key disease molecule and therapeutic target for immunotherapeutic intervention in many immune-mediated inflammatory diseases. Clinical indications include rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis. Recent clinical findings indicate that many chronic inflammatory disorders share certain pathogenic pathways, whereas others are limited to particular disease phenotypes. Better understanding of these pathogenic pathways will inform the development of new therapeutic approaches leading to more complete and sustained disease remissions.     

Interleukin-34 as a promising clinical biomarker and therapeutic target for inflammatory arthritis

Interleukin-34 (IL-34), recently identified as a novel inflammatory cytokine and the second ligand for colony-stimulating factor-1 receptor, is known to play regulatory roles in the development, maintenance, and function of mononuclear phagocyte lineage cells – especially osteoclasts. Regarding its primary effect on osteoclasts, IL-34 has been shown to stimulate formation and activation of osteoclasts, which in turn magnifies osteoclasts-resorbing activity. In addition to its role in osteoclastogenesis, IL-34 has been implicated in inflammation of synovium via augmenting production of inflammatory mediators, in which altered IL-34 expression is regulated by pro-inflammatory cytokines responsible for cartilage degradation. Indeed, IL-34 has been documented to be highly expressed in inflamed synovium of rheumatoid arthritis (RA) and knee osteoarthritis (OA) patients, which are recognized as inflammatory arthritis. Furthermore, a number of clinical studies demonstrated that IL-34 levels were significantly increased in the circulation and synovial fluid of patients with RA and knee OA. Its levels were also found to be positively associated with disease severity – especially radiographic severity of both RA and knee OA patients. Interestingly, emerging evidence has accumulated that functional blockage of IL-34 with specific antibody can alleviate the severity of inflammatory arthritis. It is therefore reasonable to speculate that IL-34 may be developed as a potential biomarker and a new therapeutic candidate for inflammatory arthritis. To date, there are numerous studies showing IL-34 involvement and association with many aspects of inflammatory arthritis. Herein, this review aimed to summarize the recent findings regarding regulatory role of IL-34 in synovial inflammation-mediated cartilage destruction and update the current comprehensive knowledge on usefulness of IL-34-based treatment in inflammatory arthritis – particularly RA and knee OA.     

MicroRNAs as a therapeutic target for cardiovascular diseases

MicroRNAs (miRNAs) are tiny, endogenous, conserved, non-coding RNAs that negatively modulate gene expression by either promoting the degradation of mRNA or down-regulating the protein production by translational repression. They maintain optimal dose of cellular proteins and thus play a crucial role in the regulation of biological functions. Recent discovery of miRNAs in the heart and their differential expressions in pathological conditions provide glimpses of undiscovered regulatory mechanisms underlying cardiovascular diseases. Nearly 50 miRNAs are overexpressed in mouse heart. The implication of several miRNAs in cardiovascular diseases has been well documented such as miRNA-1 in arrhythmia, miRNA-29 in cardiac fibrosis, miRNA-126 in angiogenesis and miRNA-133 in cardiac hypertrophy. Aberrant expression of Dicer (an enzyme required for maturation of all miRNAs) during heart failure indicates its direct involvement in the regulation of cardiac diseases. MiRNAs and Dicer provide a particular layer of network of precise gene regulation in heart and vascular tissues in a spatiotemporal manner suggesting their implications as a powerful intervention tool for therapy. The combined strategy of manipulating miRNAs in stem cells for their target directed differentiation and optimizing the mode of delivery of miRNAs to the desired cells would determine the future potential of miRNAs to treat a disease. This review embodies the recent progress made in microRNomics of cardiovascular diseases and the future of miRNAs as a potential therapeutic target - the putative challenges and the approaches to deal with it.     

Modulation of IL-33/ST2 signaling as a potential new therapeutic target for cardiovascular diseases

IL-33 belongs to the IL-1 family of cytokines, which function as inducers of Th2 cytokine production by binding with ST2L and IL-1RAcP. This, in turn, activates various signaling pathways, including the mitogen-activated protein kinase (MAPK), the inhibitor of Kappa-B kinase (IKK) pathway, and the phospholipase D-sphingosine kinase pathway. IL-33 has demonstrated protective effects against various cardiovascular diseases (CVDs) by inducing Th2 cytokines and promoting alternative activating M2 polarization. However, the soluble decoy form of ST2 (sST2) mitigates the biological effects of IL-33, exacerbating CVDs. Furthermore, IL-33 also plays a significant role in the development of asthma, arthritis, atopic dermatitis, and anaphylaxis through the activation of Th2 cells and mast cells. In this review, we aim to demonstrate the protective role of IL-33 against CVDs from 2005 to the present and explore the potential of serum soluble ST2 (sST2) as a diagnostic biomarker for CVDs. Therefore, IL-33 holds promise as a potential therapeutic target for the treatment of CVDs.     

Cytokines as potential therapeutic targets for inflammatory skin diseases

A network of pro-inflammatory cytokines is a central feature in the pathophysiology of cutaneous inflammatory diseases. Thus, the delineation of precise roles for particular cytokines and the development of cytokine-directed therapeutics have become areas of intense investigation. While anti-TNF therapeutics have proven to be effective for the treatment of psoriasis, clinical investigations have now begun with other cytokine-directed therapies, such as those targeting IFN-g, IL-12p40, and IL-18. In addition to therapeutics that target cytokines directly, strategies that target cytokine signaling pathways are in development too. In this short review, we summarize key findings from a recent workshop on cytokines as potential therapeutic targets for inflammatory skin diseases.     

SLPI and trappin-2 as therapeutic agents to target airway serine proteases in inflammatory lung diseases: current and future directions

It is now clear that NSPs (neutrophil serine proteases), including elastase, Pr3 (proteinase 3) and CatG (cathepsin G) are major pathogenic determinants in chronic inflammatory disorders of the lungs. Two unglycosylated natural protease inhibitors, SLPI (secretory leucocyte protease inhibitor) and elafin, and its precursor trappin-2 that are found in the lungs, have therapeutic potential for reducing the protease-induced inflammatory response. This review examines the multifaceted roles of SLPI and elafin/trappin-2 in the context of their possible use as inhaled drugs for treating chronic lung diseases such as CF (cystic fibrosis) and COPD (chronic obstructive pulmonary disease).     

Rho-kinase: important new therapeutic target in cardiovascular diseases

Rho-kinase (ROCKs) belongs to the family of serine/threonine kinases and is an important downstream effector of the small GTP-binding protein RhoA. There are two isoforms of Rho-kinase, ROCK1 and ROCK2, and they have different functions with ROCK1 for circulating inflammatory cells and ROCK2 for vascular smooth muscle cells. It has been demonstrated that the RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, leading to the development of cardiovascular disease. The important role of Rho-kinase in vivo has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia-reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Furthermore, the beneficial effects of fasudil, a selective Rho-kinase inhibitor, have been demonstrated for the treatment of several cardiovascular diseases in humans. Thus the Rho-kinase pathway is an important new therapeutic target in cardiovascular medicine.     

Targeting IL-34 in inflammatory autoimmune diseases

Interleukin-34 (IL-34) shares a common receptor with macrophage colony-stimulating factor (M-CSF), and can bind to CSF-1R, induces lymphocytes differentiation, proliferation, and regulates the synthesis of inflammatory components. Recent findings reported aberrant expression of IL-34 in several autoimmune disorders, such as lupus, arthritis, systemic sclerosis, inflammatory bowel diseases. The functional analysis further demonstrated that IL-34 may perform significantly in these inflammatory autoimmune disorders. IL-34 might consider as a biomarker for these diseases. I hope this collection of the findings in this review will improve knowledge of the role of IL-34, and targeting IL-34 may give the potential for these autoimmune diseases.     

Mesenchymal stem cells as therapeutic agents of inflammatory and autoimmune diseases

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Highlights? Immunomodulatory properties of MSCs in vitro and in vivo are discussed. ? Safety and efficacy of treatments with allogeneic MSCs are discussed. ? Future directions to improve efficacy of MSC treatments are proposed.     

The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases

Considerable research has been conducted on mitochondrial biology as it pertains to aging. However, relatively little attention has been accorded the pyruvate dehydrogenase complex (PDC) relative to how we grow old and acquire age-related diseases. The purpose of this review is threefold: first, to describe the physiological chemistry of the PDC and define its place in normal cellular bioenergetics; second, to compare and contrast the pathogenesis and clinical features of congenital PDC deficiency with discrete examples of age-associated dysfunction of the complex; and third, to summarize recent findings in Caenorhabditis elegans that shed additional new light on the significance of the PDC to the aging process.     

Cathepsin K: A therapeutic target for bone diseases

Cathepsin K is a member of the papain family of cysteine proteases and is highly expressed in osteoclasts that mediate bone resorption. In this review, some of the known features of cathepsin K such as structure, function in bone resorption, gene regulation and its roles in physiological or pathophysiological processes are highlighted.     

Aldose reductase: A novel therapeutic target for inflammatory pathologies

Aldose reductase (AR), that catalyzes the rate limiting step of the polyol pathway of glucose metabolism, besides reducing glucose to sorbitol, reduces a number of lipid peroxidation – derived aldehydes and their glutathione conjugates. Recent studies suggest that apart from its involvement in diabetic complications, AR's catalytic activity plays a key role in a number of inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and colon cancer. Furthermore, AR is overexpressed in human cancers such as liver, colon, breast, cervical and ovarian. Since AR inhibitors have already undergone up to phase-iii clinical trials for diabetic complications, they could be safe anti-inflammatory drugs. Therefore the future use of AR inhibitors in down-regulating major inflammatory pathologies such as cancer and cardiovascular diseases could relieve some of the major health concerns of worldwide.     

The enigmatic role of IL-38 in inflammatory diseases

IL-38 is the most recently discovered cytokine of the IL-1 family and is considered a potential inhibitor of the IL-1 and Toll-like receptor families. IL-38 exerts anti-inflammatory properties, especially on macrophages, by inhibiting secretion of pro-inflammatory cytokines, leading to reduced T-lymphocyte TH17 maturation. IL-38 has been studied most extensively in the context of chronic inflammatory diseases, particularly arthritis, where it is considered an attractive new drug candidate. IL-38 research has entered a new phase, with the realization that IL-38 is important in the pathophysiology of TH17 dependent-diseases (psoriasis, psoriatic arthritis and ankylosing spondylitis). In this review, we provide a critical evaluation of several controversial issues concerning IL-38 function and regulation. There is effectively contrasting data regarding IL-38: it is produced in conditions such as apoptosis, necrosis or inflammation, but data is lacking regarding IL-38 processing and biological function. Furthermore, the receptor for IL-38 has yet to be identified, although three candidate receptors – IL-1R1, IL-36R and IL-1RAPL1–have been proposed. Future studies will hopefully uncover new aspects of this enigmatic cytokine.     

Potential effects of HMGB1 on viral replication and virus infection-induced inflammatory responses: A promising therapeutic target for virus infection-induced inflammatory diseases

Inflammatory responses, characterized by the overproduction of numerous proinflammatory mediators by immune cells, is essential to protect the host against invading pathogens. Excessive production of proinflammatory cytokines is a key pathogenic factor accounting for severe tissue injury and disease progression during the infection of multiple viruses, which are therefore termed as “cytokine storm”. High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein released either over virus-infected cells or activated immune cells, may act as a proinflammatory cytokine with a robust capacity to potentiate inflammatory response and disease severity. Moreover, HMGB1 is a host factor that potentially participates in the regulation of viral replication cycles with complicated mechanisms. Currently, HMGB1 is regarded as a promising therapeutic target against virus infection. Here, we provide an overview of the updated studies on how HMGB1 is differentially manipulated by distinct viruses to regulate viral diseases.     

Gene expression analysis of intestinal IL-8, IL-17 A and IL-10 in patients with celiac and inflammatory bowel diseases

Molecular Biology Reports - Celiac disease (CeD) and inflammatory bowel disease (IBD) are accompanied by impaired immune responses. To study the immune regulation of these diseases, we evaluated...